The long-term goal of these studies is to understand how viruses persist and cause immune suppression at the whole animal level. Despite the remarkable advances in our knowledge about the structure and replication of many different viruses, the mechanisms by which viruses persist and damage the immune system remain poorly understood. Infection of mice with lymphocytic choriomeningitis virus (LCMV) provides an in vivo model for studying the interaction between the virus and the immune system of its natural host, and in defining conditions that lead to viral clearance or persistence. An extensive panel of in vivo selected LCMV variants that are either macrophage-tropic, lymphocyte-tropic, or amphotropic has been isolated. In contrast to the parental LCMV strain, these three types of variants establish chronic infections in adult mice suggesting that the ability to persist in vivo is due to enhanced replication in macrophages and/or lymphocytes. this conclusion is further strengthened by the finding that the variants and the parental virus grow equally well in fibroblasts and the observed growth differences are specific for cells of the immune system. The objectives of this proposal are two fold: First, to determine the molecular basis of tropism for the immune system by identifying mutations that allow viral persistence in macrophages or lymphocytes, and analyzing how these mutations affect function in a cell- specific manner. Second, to determine the importance of viral cell tropism in immune suppression. Experiments will be done to analyze the immunosuppressive potential of several independently isolated variants to determine whether preferential infection of lymphocytes and/or macrophages results in susceptibility to opportunistic infections. These studies defining viral genetic determinants of cell tropism and examining the consequences of these tropisms for persistence and immune suppression at the whole animal level, should lead to an improved fundamental understanding of the immunopathogenesis of chronic viral infections.